1. Field of the Invention
The present invention relates to poly(sialic acid) nanoparticles for use in drug delivery applications. The invention also relates to methods for treating systemic diseases and neurological disorders using poly(sialic acid) nanoparticles for drug delivery.
2. Description of the Related Art
One century ago, Paul Ehrlich proposed that drugs should be developed to selectively treat diseased cells without damaging healthy tissues. Directed by this concept, many studies have been done to investigate various materials as potential drug delivery systems for a number of diseases with broad goals of facilitating controlled release, improving efficacy, and reducing side effects. Among the different types of drug delivery systems, nanoparticles have drawn the most attention due to numerous benefits, such as reduced toxicity, as well as improved efficacy, bioavailability, and solubility. Furthermore, nanoparticles have been demonstrated to accumulate passively within tumor tissue due to the EPR (enhanced permeability and retention) effect. For systemic drug delivery, one of the most sought after properties is a long circulation time that can increase the chance of accumulation in diseased tissues, which can thereby improve drug efficacy.
Chitosan is a very popular natural polymer for drug delivery because it is non-toxic, biodegradable, biocompatible and bioadhesive. A quaternized derivative of chitosan, N,N,N-trimethyl chitosan (TMC) is soluble and positively charged regardless of pH, as opposed to chitosan that possesses a pHdependent charge. Therefore, TMC has also been widely used. To date, chitosan and its derivatives have been investigated as the basis of nanoparticles by many researchers for the delivery of low molecular weight drugs, DNA, proteins and antigens. With the presence of chitosan and/or its derivatives, a number of the latter therapeutics have shown higher uptake by diseased tissue, less toxicity, and greater specificity.
Despite these advantages, however, the application of chitosan-based nanoparticles is limited by poor stability under physiological conditions, poor efficacy in vivo, and a large size that is unfavorable for systemic drug delivery. Furthermore, due to their cationic nature, chitosan-based nanoparticles are prone to react with negatively charged components in the blood circulation, which can increase the rate of clearance by reticuloendothelial system (RES) and phagocytes. As a result, to date, few nanoparticles based upon chitosan or its derivatives are ideal for systemic drug delivery due to an overly cationic nature, a typically large size, and a propensity to aggregate.
Thus, there is a need in the art to develop nanoparticle carrier systems for drug delivery for the treatment of systemic diseases, such as rheumatoid arthritis (RA), and neuronal disorders, such as spinal cord injury (SCI) that employ a material for which the body possesses no known receptors to prevent premature clearance of the drug delivery carrier system. In addition, for drug delivery, the nanoparticles must be of proper size and charge to achieve high efficacy and low toxicity of associated therapeutics.
For example, rheumatoid arthritis is a chronic autoimmune disease characterized by inflammation of the synovial membrane that lines the non-weight bearing surface of joints. In the normal anatomy this layer provides lubrication and nourishment to the joints through the action of synovial fluid. In RA, however, this tissue becomes enlarged and inflamed eventually invading and destroying articular cartilage and bone. This condition typically begins to affect the small diarthrodal joints of the hands and feet and spreads symmetrically throughout the joints of the body to become a polyarticular arthritis. As such, rheumatoid arthritis leads to irreversible joint damage, disability, and deformity. In addition to this, those individuals diagnosed with this autoimmune condition often experience extra-articular organ involvement and, in particular, have an increased risk of ischemic heart disease and a decreased life expectancy.
Rheumatoid arthritis has been traced back several thousand years to Native American tribes in North America and is evident in European paintings that date back to the 1600s. As of 2003, RA was the most common of the more than one hundred rheumatic diseases known and currently 0.5% to 1% of the adult population worldwide suffers from this condition. Women in particular are more likely to acquire rheumatoid arthritis and there continues to be a much larger occurrence of this disease in the descendants of Native American tribes with a prevalence of up to 5%. Due to the high emotional, physical, and financial burdens this condition presents, researchers have been motivated to expend great effort in understanding the pathogenesis of rheumatoid arthritis in order to develop safer and more effective treatments. While progress has been made in understanding the complex process behind the pathogenesis of rheumatoid arthritis, the precise pathophysiological causes of RA remain largely a mystery, and therefore treatment methods have not been optimized.
Methotrexate (MTX) was originally developed in the 1950s as a cancer therapy and gained popularity as a disease modifying anti-rheumatic drug (DMARD) in the 1970s. DMARDs are able to treat rheumatoid arthritis by reducing immune function, but many are cytotoxic. Today, methotrexate is the most commonly used DMARD and in randomized controlled trials has been found to be equal or superior to all other DMARDs. In fact, for more than twenty years, the European League Against Rheumatism and the American College of Rheumatology have recommended methotrexate as a first line treatment for rheumatoid arthritis. In addition, a 60% reduction in the risk of early mortality in RA patients treated with methotrexate has been observed, as well as a 70% reduction in deaths due to RA related cardiovascular disease in individuals prescribed methotrexate.
In terms of chemical properties, methotrexate is an antimetabolite that interferes with the metabolism of folic acid, which is necessary for cell growth, and has been shown to control both symptoms and disease activity. Methotrexate enters cells through either the reduced folate carrier or folate receptor f3, which is overexpressed in rheumatoid arthritis synovial macrophages. While the mechanism of methotrexate action in the treatment of rheumatoid arthritis is uncertain, it appears to reduce the proliferation of infiltrating inflammatory cells and/or suppresses the release of pro-inflammatory cytokines.
In spite of methotrexate being the gold standard of treatment for rheumatoid arthritis, a major constraint on its use and effectiveness is the occurrence of adverse side effects. Methotrexate has been linked to several adverse reactions often associated with antimetabolites, such as cytopenia, hypersensitivity pneumonitis, bone-marrow suppression, gastrointestinal issues, and liver damage. The most common adverse effects of methotrexate are gastrointestinal problems and liver damage. Due to the hepatotoxic nature of methotrexate, patients receive periodic liver function tests and biopsies. In spite of these precautionary measures, however, cirrhosis and liver fibrosis continue to be negative consequences of methotrexate use. In fact, 3% of patients prescribed methotrexate for the treatment of rheumatoid arthritis developed severe fibrosis or cirrhosis over 55 months of treatment with methotrexate. These side effects are of greater risk in those individuals who drink at least one hundred grams of alcohol per week. All side effects of methotrexate are concerning as both potentially life-threatening and more minor side effects may lead to termination of treatment, even if therapeutic efficacy is satisfactory.
In addition to the risk of serious side effects associated with methotrexate, this drug also presents an unfavorable pharmacokinetic profile. The bioavailability and peak serum concentration of orally administered methotrexate varies between patients and elimination half-lives are inconsistent, ranging from six to fifty-five hours. The large variability in the pharmacokinetics of methotrexate likely contributes to its toxicity in some patients. Due to the high occurrence of adverse side effects and variability in drug effectiveness, the development of a method for the delivery of methotrexate in such a way as to specifically target the pannus tissue and reduce extra-organ toxicity would be a significant progression in the treatment of rheumatoid arthritis.